The present invention relates to a method of producing local anesthesia and analgesia in a nerve tissue region of a mammal by topical administration of sodium channel blocking compounds, including tetrodotoxin and/or saxitoxin.
Pain is associated with actual or potential injury or tissue damage due to inflammation, ischemia, mechanical or other irritation. Local anesthetics are used to treat pain by blocking neuronal transmission and affect sensation as well as pain. Analgesics are used to relieve pain and they additionally may interfere with the activity of chemical mediators causing inflammation.
Damage or stimulation to a sensory nerve region such as the dental pulp is usually associated with severe pain and can result from chemical or physical cause, for example, a decayed tooth, periodontitis, and surgical procedures on a tooth.
Pain induced by pulp stimulation is too severe for patients to tolerate. At present, local anesthetics are used to relieve pain, but due to their limited efficacy and short duration of action, they cannot produce a satisfactory effect on patients. For example, procaine and tetracaine are commonly prescribed as topical anesthetics for management of tooth pain. These topical anesthetics provide only partial pain relief for short periods, e.g. about 1 hour.
Therefore, there is a need in the art for methods of producing long lasting, potent anesthesia and analgesia without significant side effects.
Tetrodotoxin can be used as a local anesthetic and is ten thousand times more powerful than commonly used local non-narcotics, as is discussed by C. Y. Kao and F. A. Fulman, J. Pharmacol., 140, 31-40 (1965). Tetrodotoxin preparations in combination with other widely used anesthetics have been noted in U.S. Pat. Nos. 4,022,899 and 4,029,793. According to U.S. Pat. No. 6,030,974, xe2x80x9ctetrodotoxinxe2x80x9d or xe2x80x9cTTXxe2x80x9d refers to the amino perhydroquinazoline compounds having the molecular formula C11H17N3O8 and to derivatives thereof, including but not limited to anhydrotetrodotoxin, tetrodaminotoxin, methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin and tetrodonic acid (Kao). Examples of TTX analogs include novel TTX analogs isolated from various organisms, as well as those that are partially or totally chemically synthesized. See e.g., Yotsu, M. et al. Agric. Biol. Chem., 53(3):893-895 (1989). Such analogs bind to the same site on the alpha subunit of sodium channels as does TTX.
Adams, et al., U.S. Pat. Nos. 4.022,899 and 4,029,793 pertain to a local anesthetic composition comprising a mixture in a pharmaceutically acceptable carrier of a particular toxin, namely tetrodotoxin or desoxytetrodotoxin, and another compound, generally a conventional local anesthetic compound or a similar compound having nerve-blocking properties. The conventional local anesthetic can be an aminoacylanilide such as lidocaine, an aminoalkylbenzoate such as procaine, cocaine, an amino carbamate such as diperodon, a N-phenylamidine such as phenacine, a N-aminoalkyl amide such as dibucaine, an aminoketone such as falicain, or an aminoether such as pramoxine.
U.S. Pat. No. 6,030,974 describes a method of producing local anesthesia in a mammal experiencing pain in an epithelial tissue region. The method includes topically administering to the region, in a suitable pharmaceutical vehicle, an effective dose of a long-acting sodium channel blocking compound. The sodium channel blocking compound of U.S. Pat. No. 6,030,974 can be a formulation of tetrodotoxin or saxitoxin at a concentration of between 0.00-10 mM.
Omana-Zapata et al., Pain 72:41-49 (1997) discusses the utilization of tetrodotoxin for the inhibition of neuropathic ectopic activity in neuromas, dorsal root ganglia and dorsal horn neurons. The neuronal activity arises from neuroma caused by mechanical, chemical or ischemic injury. The effect of intravenously administered TTX on the neuronal induction by sciatic nerves in male rats was researched. However, the dosages and effects studied by Omana-Zapata et al. were applied to animals under anesthesia and artificial ventilation, thus these doses are above the maximal tolerated dose and the administration was under conditions that are not applicable to the presently intended clinical use of tetrodotoxin.
Topical administration of any sodium channel blocking compound to the vicinity of the teeth is not described in any of the above instances.
The methods and compositions of the present invention solve the long-recognized need in the art for methods of producing potent local anesthesia and analgesia of long duration. In the particular embodiment of producing long-lasting potent local anesthesia and analgesia on the tooth, the inventors have addressed a problem of great clinical significance, showing for the first time that sodium channel blocking compounds, such as tetrodotoxin and saxitoxin, can produce potent analgesic and anesthesia effects on pain induced by pulp stimulation of long duration and without evident side effects. Moreover, the inventors have shown that the effective doses of those sodium channel-blocking compounds have a wide margin of safety.
The methods and compositions of the invention can be used for any condition involving tooth pain, including local anesthesia following tooth surgery, and following injury to the tooth. The methods provide significant advantages, including providing at least 1 hour, preferably 2 hours and most preferably 6 hours of local anesthesia and analgesia, without evident side effects.
The present invention includes methods of producing potent long-lasting local anesthesia and analgesia, comprising administering a pharmaceutically acceptable composition of a long-acting sodium channel blocking compound, wherein the compound binds to the extracellular mouth of the sodium channel. In this manner sodium channel activity is inhibited by a mechanism distinct from that of local anesthetics, such as procaine, lidocaine and tetracaine. Preferably, such methods achieve potent local analgesia and anesthesia of long duration up to 6 hours. Preferred compounds include toxins or analogs thereof that specifically bind to a site formed in part by an extracellular region of the alpha subunit of a sodium channel. Most preferred compounds comprise the class of toxins and analogs that specifically bind to a site formed by the SS1 and SS2 extracellular regions of the alpha sub-unit of a sodium channel, wherein such compounds include tetrodotoxin, saxitoxin and analogs thereof. Surprisingly, these long-acting sodium channel blocking compounds, which are well known potent neurotoxins, provide potent long-lasting local analgesia and anesthesia without evident side-effects.
Accordingly, it is an object of the invention to provide a method of producing potent local analgesia and anesthesia in patients experiencing pain such as that associated with damage to tooth pulp, such as a decayed tooth, periodontitis and surgical procedures on a tooth.
In one aspect, the invention includes a method of producing potent local analgesia and anesthesia in a subject experiencing pain in the tooth pulp.
The invention lies partly in a method of producing local analgesia or anesthesia in nerve tissue of a mammal experiencing pain caused by damage to or stimulation of the nerve tissue. The method comprises administering to the nerve tissue of the mammal an anesthetically or analgesically effective dose of a pharmaceutical composition comprising a compound that binds to the SS1 or SS2 subunit of a sodium channel and a pharmaceutically suitable vehicle. The nerve tissue region can be a dental pulp region, a trigeminal nerve region, or a sciatic nerve region.
The method includes topically administering to the tooth pulp cavity, in a suitable pharmaceutical vehicle, an effective dose of tetrodotoxin or saxitoxin or analogs thereof.
In one embodiment, the effective dose of tetrodotoxin or saxitoxin is administered from a formulation containing tetrodotoxin or saxitoxin at a concentration of between 1 mM to 20 mM which causes a pain reducing effect for up to 6 hours.
In this application, tetrodotoxin is typically formulated in a vehicle having a pH of between 3.5 to 6.8.
In this application, the pharmaceutical composition does not produce toxic effects or any obvious deleterious side effects.
The present invention also includes a composition comprising a conventional local anesthetic compound that is a sodium channel blocking compound and a compound that binds to the SS1 or SS2 subunit of a sodium channel. The composition of the invention provides a synergistic effect of its component compounds to provide either or both of a more potent or a longer anesthetic effect.